High-fat-diet-induced remission of diabetes in a subset of K_ATP -GOF insulin-secretory-deficient mice.

AIMS:To examine the effects of a high-fat-diet (HFD) on monogenic neonatal diabetes, without the confounding effects of compensatory hyperinsulinaemia. METHODS:Mice expressing K_ATP channel gain-of-function (K_ATP -GOF) mutations, which models human neonatal diabetes, were fed an HFD. RESULTS:Surprisingly, K_ATP -GOF mice exhibited resistance to HFD-induced obesity, accompanied by markedly divergent blood glucose control, with some K_ATP -GOF mice showing persistent diabetes (K_ATP -GOF-non-remitter [NR] mice) and others showing remission of diabetes (K_ATP -GOF-remitter [R] mice). Compared with the severely diabetic and insulin-resistant K_ATP -GOF-NR mice, HFD-fed K_ATP -GOF-R mice had lower blood glucose, improved insulin sensitivity, and increased circulating plasma insulin and glucagon-like peptide-1 concentrations. Strikingly, while HFD-fed K_ATP -GOF-NR mice showed increased food intake and decreased physical activity, reduced whole body fat mass and increased plasma lipids, K_ATP -GOF-R mice showed similar features to those of control littermates. Importantly, K_ATP -GOF-R mice had restored insulin content and β-cell mass compared with the marked loss observed in both HFD-fed K_ATP -GOF-NR and chow-fed K_ATP -GOF mice. CONCLUSION:Together, our results suggest that restriction of dietary carbohydrates and caloric replacement by fat can induce metabolic changes that are beneficial in reducing glucotoxicity and secondary consequences of diabetes in a mouse model of insulin-secretory deficiency.

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